This invention is related to amidino derivatives of the formula (I), non-toxic salts thereof, hydrates thereof, processes for the preparation thereof, and the blood coagulation factor VIIa inhibitors containing the derivatives as active ingredient.
More particularly, this invention is related to amidino derivatives of the formula (I) 
wherein all the symbols are as hereinafter defined, non-toxic salts thereof, hydrates thereof, processes for the preparation thereof, and the blood coagulation factor VIIa inhibitors containing the derivatives as active ingredient.
The blood coagulation is a protective reaction which is caused by vascular injury or irritate stimulus with endotoxin or the other foreign bodies. This reaction proceeds on the membrane of platelets which aggregate at the injured site or on the membrane of injured endothelial cells and it requires Ca ion. The blood coagulation system contains eight kinds of serine proenzymes (e.g. plasma prekallikrein factor XII, factor XI, factor VII, factor IX, factor X, prothrombin, protein C), five protein co-factor (e.g. macromolecule kininogen, tissue factor, factor VIII, factor V, protein S), and a fibrillar protein, fibrinogen. xcex1-Thrombin produced by the coagulation cascade give information to endothelial cells and form insoluble fibrin gel. The scheme of the blood coagulation cascade is shown below. 
The blood coagulation cascade consists of the intrinsic pathway and the extrinsic pathway. The intrinsic pathway acts on foreign surface charged negatively. However, foreign surface in the body is uncertain, so the significance of the intrinsic pathway in hemostasis is not established. On the other hand, the extrinsic pathway is triggered by the complex formation of the blood coagulation factor VIIa (FVIIa) and tissue factor which is expressed by a vascular damage or the presence of endotoxin. This pathway confluents with the intrinsic pathway at a point of factor X and factor IX activation.
The extrinsic pathway seems to be more important than the intrinsic pathway in the physiologic condition (hemostasis) or pathological condition (thrombosis). The reasons are as follows.
1) The presence of tissue factor (TF) is recognized in physiological condition.
2) The expression of TF is induced by endotoxin on the membrane of vascular endothelial cells or/and monocytes.
3) Since TF is observed on foam cells in the plaque of arteriosclerosis, the extrinsic pathway is considered to contribute the topical coagulation activity.
Warfarin, an anticoagulant agent, inhibits the production of various factors, including protein C and S. Thrombin inhibitors such as heparin, which act at the downstream of a coagulation cascade, may inhibit blood coagulation excessively and do not inhibit the consumption of coagulation factors. Because of these reasons, bleeding tendency is the main problem in clinic.
On the other hand, FVIIa is located at the top site of the cascade in the extrinsic pathway. Therefore, FVIIa inhibitors inhibit the extrinsic pathway, leaving intact the activity of the intrinsic pathway.
Consequently, FVIIa inhibitors are different from thrombin inhibitors leaving a function of the intrinsic pathway. It is considered that FVIIa inhibitors have a resistance to bleeding, then it is expected to be able to reduce a bleeding tendency as a side effect.
FVIIa inhibitors suppress a coagulation activity of the extrinsic pathway, and then they are useful for treatment and/or prevention for several thormbotic diseases triggered by the extrinsic pathway. For example, several angiopathy caused by enhancing a coagulation activity, such as disseminated intravascular coagulation, coronary thrombosis (e.g. acute myocardial infarction, unstable angina), cerebral infarction, cerebral embolism, transient ischemic attack, cerebrovascular disorders, pulmonary vascular diseases (e.g. pulmonary infarction, pulmonary embolism), deep venous thrombosis, peripheral arterial obstruction, thrombosis after artificial vascular transplantation and artificial valve transplantation, post-operative thrombosis, reobstruction and restenosis after coronary artery bypass operation, reobstruction and restenosis after PTCA (percutaneous transluminal coronary angioplasty) or PTCR (percutaneous transluminal coronary recanalization), thrombosis by extracorporeal circulation and procoagulative diseases such as glomerlonephriitis.
(1) In the specification of WO 9620689, boric acid derivatives of the formula (A):
R1Axe2x80x94ZAxe2x80x94CHR2Axe2x80x94AAxe2x80x83xe2x80x83(A)
wherein AA is xe2x80x94BY1AY2A, in which YA1 and y2A each independently, is xe2x80x94OH, C1-8 alkoxy; xe2x80x94COOR3A, in which R3A is hydrogen, C1-8 alkyl; R2A is 
in which pA is 0-2, qA is 0-4, XA is C(NH)NHR14A, in which R14A is hydrogen, C1-4 alkyl; ZA is (CH2)mACONR8A, (CH2)mACSNR8A, (CH2)mASO2NR8A, (CH2)mACO2, (CH2)mACSO, (CH2)mASO2O, R8A is hydrogen, C1-8 alkyl, mA is 0-6, R1A is (CH2)PAaryl, in which pA is 0-2, aryl is phenyl, naphthyl, biphenyl, and they may be substituted by 1-3 of (CH2)WACO2R8A, (CH2)WACNR8AR9A; WA is 0-5, R8A and R9A is hydrogen, C1-8 alkyl; with the proviso that explanations of each inhibitory activity of thrombin, Fxa, FVIIa.
(2) In the specification of WO 9429273, the compound of the formula (B): 
wherein A1B to A4B form a substituted 6 membered ring optionally unsaturated, and optionally containing up to two hetero atoms selected from O, S and N;
D1B to D4B form a substituted 6 membered aromatic ring optionally containing up to two nitrogens, D1B-D4B is CR11B or N; RB is at least one substituent selected from R7, QBxe2x80x94C1-4 alkyl, QBxe2x80x94C2-4 alkenyl and QBxe2x80x94C2-4 alkynyl;
R*B is hydrogen, QBxe2x80x94C1-6 alkyl, ArB or HetB;
QB is hydrogen, C3-6 cycloalkylHetB or ArB;
R6B is WBxe2x80x94(CRxe2x80x2B2)qBxe2x80x94ZBxe2x80x94(CRxe2x80x2BR10B)rBxe2x80x94UBxe2x80x94(CRxe2x80x2B2)sBxe2x80x94VBxe2x80x94;
R7B is xe2x80x94COR8B, xe2x80x94PO(ORxe2x80x2B)2 and TetB;
R8B is xe2x80x94ORxe2x80x2B, xe2x80x94NRxe2x80x2BRxe2x80x3B, xe2x80x94NRxe2x80x2BORxe2x80x2B;
R10B is hydrogen, C1-4 alkyl or xe2x80x94NRxe2x80x2BRxe2x80x3B;
R11B is QBxe2x80x94C0-6 alkyl;
Rxe2x80x2B, Rxe2x80x3B are hydrogen, C1-6 alkyl, C3-7 cycloalkyl-C0-4 alkyl, or ArBxe2x80x94C0-4 alkyl;
UB and VB is absent or CONRxe2x80x2B, NRxe2x80x2BCO, S(O)nBNRxe2x80x2B, NRxe2x80x2BS(O)nB, NRxe2x80x2BCRxe2x80x2B2,
CRxe2x80x2B2NRxe2x80x2B, CRxe2x80x2B2O, OCRxe2x80x2B2, Cxe2x89xa1C, CRxe2x80x2Bxe2x95x90CRxe2x80x2B;
WB is 
YB is absent, S or O;
ZB is (CH2)tB, HetB, ArB or C3-7 cycloalkyl;
nB is 0-3; qB is 0-3; rB is 0-2; sB is 0-2; tB is 0-2; with the proviso that explanations of each groups were disclosed only necessary parts; or salts thereof are described to possible an inhibitory activity of fibrinogen receptor GPIIb/IIIa.
In the specification of WO 9300095 and WO 9412478, similarity compounds are described to possible an inhibitory activity of fibrinogen receptor GPIIb/IIIa.
(3) In the specification of WO 9730971, the compound of the formula (C): 
wherein DC is CN, C(=NR7C)NR8CR9C, NHC(=NR7C)NR8CR9C, NR8CCH(=NR7C) etc.; EC is phenyl, 2-pyridyl, 4-pyridyl, etc.; RaC is a single bond or CHxe2x95x90CH; RbC is C(O)RC or GC; GC is hydrogen, OG1C, SG1C, NG1CG2C, etc.; G1C is hydrogen, C1-6 alkyl; G2C is hydrogen, C1-6 alkyl; RC is hydrogen, OH, C1-6 alkoxy, etc.; R7C is hydrogen, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, etc.; R8C and R9C are hydrogen, C1-6 alkyl, (CH2)n-phenyl; XC is CHCH(R1C), N, etc.; ZC is (CH2)n, C(xe2x95x90O), etc.; pC is 1-4; AC is benzyl, C3-10 carbocyclic ring, 5-10 membered heterocyclic ring; BC is hydrogen, C1-6 alkyl, benzyl, C3-10 carbocyclic ring, 5-10 membered heterocyclic ring; are described to possible an inhibitory activity of FXa.
Energetic investigations have been carried out in order to make the blood coagulation factor VIIa inhibitors. The present inventors have found that the present compound of the formula (I) accomplished the present purpose.
The present invention is related to amidino derivatives of the formula (I): 
wherein R1 and R2 each independently, is
1) hydrogen,
2) hydroxy,
3) C1-4 alkoxycarbonyl,
4) C2-4 alkenyloxycarbonyl,
5) C1-4 alkoxycarbonyloxy or
6) xe2x80x94COOxe2x80x94(C1-4 alkyl)-phenyl,
xe2x80x83when R2 is group excepting hydrogen, R2 is hydrogen, or when R2 is group excepting hydrogen, R1 is hydrogen;
R3 is
1) hydrogen,
2) C1-4 alkyl,
3) hydroxy,
4) xe2x80x94Oxe2x80x94(C1-4 alkyl)-phenyl, or
5) halogen atom;
E1 ring is
1) 5-7 membered unsaturated carbocyclic ring or
2) 5-7 membered unsaturated heterocyclic ring;
E2 ring is
1) 5-7 membered unsaturated carbocyclic ring or
2) 5-7 membered unsaturated heterocyclic ring;
E3 ring is
1) absent,
2) 5-7 membered unsaturated or saturated carbocyclic ring or
3) 5-7 membered unsaturated or saturated heterocyclic ring;
E4 ring is
1) 5-6 membered unsaturated carbocyclic ring or
2) 5-6 membered unsaturated heterocyclic ring;
R4 and R5 each independently is
1) xe2x80x94COOR8, in which R8 is hydrogen, C1-8 alkyl, xe2x80x94(C1-4 alkyl)-phenyl or xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl);
2) xe2x80x94(C1-4 alkyl)xe2x80x94COOR9, in which R9 is hydrogen, C1-8 alkyl, xe2x80x94(C1-4 alkyl)-phenyl or xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl);
3) xe2x80x94(C2-4 alkenyl)-COOR10, in which R10 is hydrogen, C1-8 alkyl,xe2x80x94(C1-4 alkyl)-phenyl or xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl);
4) xe2x80x94Oxe2x80x94(C1-4 alkyl)-COOR11, in which R11 is hydrogen, C1-8 alkyl, xe2x80x94(C1-4 alkyl)-phenyl or xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl);
5) xe2x80x94CONR12R13, in which R12 is hydrogen, C1-4 alkyl, R13 is hydroxy, xe2x80x94Oxe2x80x94(C1-4 alkyl)-phenyl or cyano;
6) xe2x80x94P(O)(OR14)2, in which R14 is hydrogen, C1-4 alkyl or xe2x80x94(C1-4 alkyl)-phenyl; or
7) tetrazol-5-yl which is optionally substituted by C1-8 alkyl; p and q each independently, is 0 or 1-2, with the proviso that p+q is 1 or 2;
R6 and R7 each independently, is
1) hydrogen,
2) C1-8 alkyl,
3) nitro,
4) cyano,
5) halogen atom,
6) xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl)-phenyl,
7) xe2x80x94NR15R16, in which R15 and R16 each independently, is hydrogen or C1-8 alkyl;
8) xe2x80x94OR17, in which R17 is hydrogen, C1-8 alkyl, CF3, C2-5 acyl, xe2x80x94(C1-4 alkyl)-phenyl, xe2x80x94(C1-4 alkyl)xe2x80x94OH, xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl), or xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl);
9) xe2x80x94(C1-4 alkyl)xe2x80x94OR17, in which R17 is as hereinbefore defined
10) xe2x80x94J1xe2x80x94J2, in which J1 is
(1) xe2x80x94CONR18xe2x80x94, in which R18 is hydrogen or C1-4 alkyl;
(2) xe2x80x94NR19COxe2x80x94, in which R19 is hydrogen or C1-4 alkyl;
(3) xe2x80x94SO2NR20xe2x80x94, in which R20 is hydrogen or C1-4 alkyl;
(4) xe2x80x94NR21SO2xe2x80x94, in which R21 is hydrogen or C1-4 alkyl;
(5) xe2x80x94(C1-4 alkyl)xe2x80x94NR22xe2x80x94, in which R22 is hydrogen or C1-4 alkyl;
(6) xe2x80x94COxe2x80x94,
(7) xe2x80x94(C1-4 alkyl)xe2x80x94NR23COxe2x80x94, in which R23 is hydrogen or C1-4 alkyl;
J2 is
(1) C1-15 alkyl optionally substituted by 1-3 of following groups (i)-(x):
(i) C3-7 cycloalkyl optionally substituted by xe2x80x94(C1-4 alkyl)xe2x80x94OR24;
(ii) phenyl,
(iii) 5-7 saturated heterocyclic ring optionally substituted by carboxyl or C1-4 alkoxycarbonyl;
(iv) OR24, in which R24 is hydrogen, C1-4 alkyl, xe2x80x94COOxe2x80x94(C1-4 alkyl)-phenyl, C2-5 acyl, or xe2x80x94(C1-4 alkyl)-phenyl;
(v) NR25R26, in which R25 is hydrogen or C1-4 alkyl, R26 is hydrogen, C1-4 alkyl, xe2x80x94COO(C1-4 alkyl)-phenyl, imino(C1-4 alkyl) or C1-4 alkoxycarbonyl;
(vi) xe2x80x94S(O)rxe2x80x94(C1-4 alkyl), in which r is 0-2;
(vii) xe2x80x94COOR27, in which R27 is hydrogen, C1-4 alkyl or xe2x80x94(C1-4 alkyl)-phenyl;
(viii) xe2x80x94CONR28R29, in which R28 and R29 each independently, is
xe2x80x83(i) hydrogen, (ii) C1-4 alkyl, (iii) hydroxy, or (iv) C1-4 alkyl substituted by one of hydroxy, phenyl or NR25R26, or R28 and R29 taken together with the nitrogen atom to which they are attached form 5-6 membered saturated heterocyclic ring containing nitrogen atom;
(ix) halogen atom,
(x) trihalomethyl;
(2) C2-8 alkenyl,
(3) C5-7 cycloalkyl optionally substituted by 1-3 of C1-4 alkyl, xe2x80x94COOR27, in which R27 is as hereinbefore defined; xe2x80x94(C1-4 alkyl)xe2x80x94OR24, in which R24 is as hereinbefore defined;
(4) xe2x80x94NR25R26, in which R25 and R26 is as hereinbefore defined;
(5) 5-6 membered saturated heterocyclic ring optionally substituted by 1-3 of C1-4 alkyl, oxo, imino(C1-4 alkyl); or R18 and J2 taken together with the nitrogen atom to which they are attached form saturated heterocyclic ring optionally substituted by 1-3 of C1-8 alkyl, C2-8 alkenyl or xe2x80x94COOR27, in which R27 is hereinbefore defined;
m is 1-3;
n is 1-3;
two R6 taken together with the neighboring two carbon of E4 ring to which they are attached form 5-6 membered unsaturated carbocyclic ring or 5-6 membered saturated heterocyclic ring, that rings may be substituted by 1-3 of R4 or R6;
A is
1) ethylene,
2) vinylene,
3) ethynylene,
4) xe2x80x94Oxe2x80x94CH2xe2x80x94,
5) xe2x80x94CH2xe2x80x94Oxe2x80x94,
6) xe2x80x94NR30COxe2x80x94, in which R30 is hydrogen or C1-4 alkyl;
7) xe2x80x94NR31CHR32xe2x80x94, in which R31 is hydrogen or C1-4 alkyl, R32 is hydrogen, cyano, COOR36, in which R36 is hydrogen or C1-4 alkyl; or CONR37R38, in which R37 and R38 each independently, is hydrogen or C1-4 alkyl;
8) xe2x80x94CH2xe2x80x94NR33xe2x80x94, in which R33 is hydrogen or C1-4 alkyl;
9) xe2x80x94Sxe2x80x94CH2xe2x80x94;
10) xe2x80x94CH2xe2x80x94Sxe2x80x94,
11) xe2x80x94SO2NR34xe2x80x94, in which R34 is hydrogen or C1-4 alkyl;
12) xe2x80x94NR35SO2xe2x80x94, in which R35 is hydrogen or C1-4 alkyl; non-toxic salts thereof, or hydrates thereof,
(2) the blood coagulation factor VIIa inhibitors containing the compound of formula (I) as active ingredient,
(3) processes for the preparation of the compound of formula (I).
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkoxy and alkylene include straight and branched isomers. Isomers based on double bond, ring, fused ring (E, Z, cis, trans), isomers resulting from the presence of asymmetric carbon(s) (R-configuration, S-configuration, xcex1-configuration, xcex2-configuration, enantiomers, diastereoisomers), optically active compound having optical rotation (D, L, d, l-configuration), polar compounds obtained by chromatographic separations (high polar compound, low polar compound), equilibrium compounds, the mixtures are existed by free ratio, racemic mixtures are included in the present invention.
In the compound of the formula (I),
C1-4 alkyl represented by R3, R12, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R33, R34, R35, R36, R37, R38,
C1-4 alkyl in xe2x80x94COOxe2x80x94(C1-4 alkyl)-phenyl represented by R1, R2, R24, R26,
C1-4 alkyl in xe2x80x94Oxe2x80x94(C1-4 alkyl)-phenyl represented by R3, R13,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)-phenyl represented by R8, R9, R10, R11, R14, R17, R27, R28, R29,
C1-4 alkyl in xe2x80x94(C14 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl) represented by R8, R9, R10, R11, R17,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94COOR9 represented by R4, R5,
C1-4 alkyl in xe2x80x94Oxe2x80x94(C1-4 alkyl)xe2x80x94COOR11 represented by R4, R5,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl)-phenyl represented by R6, R7,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94OH represented by R17, R28, R29,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl)xe2x80x94Oxe2x80x94(C1-4 alkyl) represented by R17,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94NR22xe2x80x94represented by J1,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94NR23COxe2x80x94 represented by J1,
C1-4 alkyl in xe2x80x94S(O)rxe2x80x94(C1-4 alkyl) represented in J2,
C1-4 alkyl in J2,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94R24 represented in J2,
C1-4 alkyl in xe2x80x94imino(C1-4 alkyl) represented in J2 and by R26,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94OR17 represented by R6, R7,
C1-4 alkyl in xe2x80x94(C1-4 alkyl)xe2x80x94NR25, R26 represented by R28, R29 is methyl, ethyl, propyl, butyl and isomeric groups thereof.
C1-8 alkyl represented by R6, R7, R8, R9, R10, R11, R15, R16, J2, C1-8 alkyl as substituents of heterocyclic ring containing nitrogen atom and tetrazol ring represented by R4, R5 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof.
C1-4 alkoxy in C1-4 alkoxycarbonyl represented by R1, R2, C1-4 alkoxy in C1-4 alkoxycarbonyloxy represented by R1, R2, C1-4 alkoxy in C1-4 alkoxycarbonyl as substituents of 5-7 membered saturated hetercyclic ring represented by J2 is methoxy, ethoxy, propoxy, butoxy and isomeric groups thereof.
C2-4 alkenyl in C2-4 alkenyloxycarbonyl represented by R1, R2, C2-4 alkenyl in xe2x80x94(C2-4 alkenyl)xe2x80x94COOR10 represented by R4, R5 is ethenyl, propenyl, butenyl and isomeric groups thereof.
Halogen atom represented by R6, R7 is fluorine, chlorine, bromine or iodine.
Trihalomethyl in J2 is methyl substituted by 3 of halogen atoms that is fluorine, chlorine, bromine or iodine.
C3-7 cycloalkyl as substituents in J2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
C5-7 cycloalkyl as substituents in J2 is cyclopentyl, cyclohexyl or cycloheptyl.
C2-5 acyl represented by R17, R24 is acetyl, propionyl, butyryl, valeryl and isomeric groups thereof.
5-7 membered unsaturated carbocyclic ring represented by E1, E2, E3 is cyclopentadiene, benzene, cycloheptatriene, etc. 5-7 membered saturated carbocyclic ring represented by E3 is cyclopentadane, cyclohexane, cycloheptane. 5-6 membered unsaturated carbocyclic ring represented by E4, and 5-6 membered unsaturated carbocyclic ring formed by two R6 is cyclopentadiene, benzene.
5-7 membered unsaturated or saturated heterocyclic ring represented by E1, E2, E3, 5-7 membered saturated heterocyclic ring in J2, means 5-7 membered unsaturated or saturated heterocyclic ring containing 1-2 of hetero atom(s) selected by oxygen, sulfur and/or nitrogen.
For example, 5-7 membered unsaturated or saturated heterocyclic ring containing 1-2 of hetero atom(s) selected by oxygen, sulfur and/or nitrogen is piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiain (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine.
5-6 membered unsaturated heterocyclic ring represented by E4 means 5-6 membered saturated heterocyclic ring containing one of oxygen, sulfur or nitrogen, for example, furan, thiophene, pyrrole, pyridine.
5-6 membered saturated heterocyclic ring represented by J2 means 5-6 membered saturated heterocyclic ring containing 1-2 of hetero atom(s) selected by oxygen atom, sulfur atom and/or nitrogen atom, for example, oxolane, oxane, pyrrolidine, piperidiene, dioxolane, dioxane, imidazolidine, pyrazolidine, piperazine, morpholine.
A saturated heterocyclic ring containing nitrogen formed by R18 and J2 taken together with the nitrogen atom to which they are attached, or R28 and R29 taken together with the nitrogen atom to which they are attached means 5-6 membered saturated heterocyclic ring containing one nitrogen, two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur, for example, pyrrolidine, piperidine, imidazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine.
5-6 membered saturated heterocyclic ring formed by two R6 taken together with the neighboring two carbon of E4 ring to which they are attached means 5-6 membered saturated heterocyclic ring containing 1-2 of hetero atom(s) of oxygen, sulfur and/or nitrogen, for example, oxolane, oxane, pyrrolidine, piperidiene, thiolane, thiane, dioxolane, dioxane, imidazolidine, pyrazolidine, dithiolane, dithiane, piperazine, oxathiane, morpholine, thiomorpholine.
In the formula (I), the ring represented by 
means E3 ring is absent, that is only E2 ring represents ring, and both of E2 ring and E3 ring represent ring, for example, benzene, naphthalene, 1,2,3,4-tetrahydronaphthalene, indan, benzofuran, 2,3-dihydrobenzofuran, benzoimidazole, 1,3-dioxaindan, benzothiophene, pyridine, pyrimidine, isoquinoline, thiophene, furan. Especially preferable group is benzene, pyridine, thiophene, furan.
In the formula (I), as ring represented by 
benzene, naphthalene, 2,3-dihydrobenzofuran, 1,3-dioxaindan, pyridine, furan, thiophen are preferable. Especially preferable group is benzene, pyridien, furan, thiophene.
In the formula (I), all groups represented by R4 and R5 are preferable. Especially preferable group is COOR8.
Besides, especially preferable attachment point on E4 ring of one R4 is ortho position.
In the formula (I), all groups represented by R6 are preferable. Especially preferably, at least one of R6 is xe2x80x94J1xe2x80x94J2.
In the formula (I), all groups represented by R7 are preferred. Especially preferably, at least one of R7 is hydrogen, C1-4 alkyl, nitro, NR15R16, OR17, xe2x80x94(C1-4 alkyl)xe2x80x94OR17.
In the formula (I), all groups represented by A are preferable. Especially preferable groups are xe2x80x94CH2xe2x80x94Oxe2x80x94, NR30COxe2x80x94, xe2x80x94NR31CHR32xe2x80x94.
In the compound of the formula (I), the compound of the formula 
and the compound of the formula 
are equivalence, and the compound of the formula 
and the compound of the formula 
are equivalence.

In the compounds of the present invention of formulae (I), the compounds of the formula (I-1): 
wherein Aa is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94N30COxe2x80x94 in which R30 is as hereinbefore defined; xe2x80x94NR31CHR32xe2x80x94 in which R31 and R32 are as hereinbefore defined; pp and qq each independently, is 0-1, with the proviso that pp+qq is 0 or 1, the other symbols are as hereinbefore defined, with the provisio that Aa and E4 ring attach to E2 ring at ortho position, E2 ring and essential one R4 attach to E4 ring at ortho position; are preferable.
The following compounds of the formulae are especially preferable: the formula (Ia): 
wherein all the symbols are as hereinbefore defined;
the formula (Ib): 
wherein all the symbols are as hereinbefore defined;
the formula (Ic): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (Id): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (Ie): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (If): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (Ig): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (Ih): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
the formula (Ii): 
xe2x80x83wherein all the symbols are as hereinbefore defined;
non-toxic salts thereof, or hydrates thereof.
As the specific compounds described in Table 1-Table 27, non-toxic salts thereof and hydrates thereof, and the compounds described in the Examples are preferable.
The following compounds include isomers resulting from the presence of asymmetric carbon(s), that is R-configuration, S-configuration and RS-configuration are also included.
Salts
Non-toxic salts of the present invention include all pharmaceutically acceptable salts.
The compounds of formulae (I) of the present invention may be converted into the corresponding salts. Non-toxic salts and water-soluble salts are preferred. Suitable salts, for example, include: salts of alkali metals (e.g. potassium, sodium), salts of alkaline earth metals (e.g. calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, dicyclohexylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine).
The compounds of formulae (I) may be converted into the corresponding acid addition salts. Non-toxic acid addition salts and water-soluble acid addition salts are preferred. Suitable salts, for example, include: salts of inorganic acids e.g. hydrochloride, hydrobromide, sulfate, phosphate, nitrate; salts of organic acids e.g. acetate, trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethionate, glucuronate, gluconate.
The compounds of formulae (I) and salts thereof may be converted into the corresponding hydrates by conventional manner.
Process for the Preparation of the Present Compound
(a-1) In the compound of the present invention of the formula (I), the compound in which A is xe2x80x94NR30COxe2x80x94, and R1, R2 and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including amino and are optionally protected hydroxy, E4 ring is not pyrrole, furan and thiophene, that is the compound of the formula (I-A-1): 
wherein
R1-1, R2-1 and R3-1 each independently, is a same meaning as R1, R2 and R3, with the proviso that in the case of R1, R2 and R3 are groups including hydroxy, then the hydroxy represented by corresponding R1-1, R2-1 and R3-1 is protected hydroxy,
R4-1 is a same meaning as R4 excepting CONR12R13, with the proviso that in the case of R4 is groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl, then xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl represented by corresponding R4-1 are protected xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl,
R5-1 is a same meaning as R5 excepting CONR12R13, with the proviso that in the case of R5 is groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl, then xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl represented by corresponding R5-1 are protected xe2x80x94COOH, P(O)(OH)2 and tetrazol-5yl,
R6-1 and R7-1 are a same meaning as R6 and R7, with the proviso that in the case of R6 and R7 are groups including hydroxy and amino, then the hydroxy and amino represented by corresponding R6-1 and R7-1 are hydroxy or protected hydroxy and protected amino,
A1 is xe2x80x94NR30CHOxe2x80x94,
E4a ring is a same meaning as E4, with the proviso that it is not pyrrole, furan and thiophene, the other symbols are as hereinbefore defined;
may be prepared by amidation the compound of the formula (II): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (III): 
wherein all the symbols are as hereinbefore defined;
or in the case of the compound in which R6-1 and R7-1 are the group containing protected hydroxy, continually, may be prepared by deprotection.
The method of amidation is known. It includes the method
(1) via an acyl halide,
(2) via a mixed acid anhydride,
(3) using a condensing agent.
These methods are explained as follows.
(1) The method via an acyl halide, for example, may be carried out in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran, ethyl acetate) or without a solvent, using an acyl halide (e.g. oxalyl chloride or thionyl chloride) at xe2x88x9220xc2x0 C. to reflux temperature, and the obtained acyl halide derivative may be reacted with an amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of a tertiary amine (e.g. pyridine, triethyl amine, dimethyl aniline or dimethylaminopyridine) at 0-40xc2x0 C.
(2) The method via a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g. pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) or without a solvent, in the presence of a tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, N-methylmorpholine) at xe2x88x9220xc2x0 C.-40xc2x0 C., and the obtained mixed acid anhydride derivative may be reacted with a corresponding amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) at 0-40xc2x0 C.
(3) The method using a condensing agent (e.g. 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) or 2-chloro-1-methylpyridinium iodide, 1,1xe2x80x2-carbonyldiimidazole (CDI)) may be carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (e.g. chloroform, methylene chloride, dimethylformamide, diethyl ether, tetrahydrofuran) or without a solvent, optionally in the presence of a tertiary amine (e.g. pyridine, triethylamine, dimethylaniline or dimethylaminopyridine) using a condensing agent, using 1-hydroxybenzotriazole (HoBt) or without HoBt at 0-40xc2x0 C.
The reaction described in (1), (2) and (3) may be carried out under an inert gas (e.g. argon, nitrogen) to avoid water in order to obtain a preferable result.
The deprotection of hydroxy is known, for example, it includes the method deprotection under acidic conditions or hydrogenolysis.
Deprotection under acidic conditions, for example, may be carried out in a solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate, anisole) or without solvent, using an organic acid (e.g. acetic acid, trifluoroacetic acid, methansulfonic acid, trimethylsilyl iodide), or an inorganic acid (e.g. hydrogen chloride) or a mixture thereof (e.g. hydrogen bromide acetic acid) at 0-90xc2x0C.
Hydrogenolysis, for example, may be carried out in a solvent (e.g. tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, methanol, ethanol), in the presence of a catalyst (e.g. palladium on carbon, palladium, palladium hydroxide, palladium acetate, palladium black, platinum black, nickel or Raney-nickel), at ordinary or elevated pressure of hydrogen gas at 0-80xc2x0 C.
(a-2) In the compound of the present invention of the formula (I), the compound in which A is xe2x80x94NR30CHOxe2x80x94, and R1, R2 and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, E4 ring is pyrrole, furan or thiophene, that is the compound of the formula (I-A-2): 
wherein
E4b is pyrrole, furan or thiophene,
R6-2 and R7-2 are a same meaning as R6 and R7, with the proviso that in the case of R6 and R7 are groups including hydroxy and amino, then the hydroxy and amino represented by corresponding R6-2 and R7-2 are protected hydroxy and protected amino, the other symbols are as hereinbefore defined;
may be prepared by subjecting to condensation reaction, the compound of the formula (XI-a): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (IX):
H2Nxe2x80x94R1xe2x80x83xe2x80x83(IX)
wherein R1 is as hereinbefore defined.
The condensation reaction is known, for example, it may be carried out by reacting with the compound of the formula (IX) or salt thereof in organic solvent (e.g. methanol, ethanol, acetonitrile, methylene chloride, diethyl ether, tetrahydrofuran, toluene, dimethylformamide) without a solvent, optionally in the presence of an base (e.g. triethylamine, sodium hydride, sodium methoxide, sodium ethoxide) at 0xc2x0 C. to reflux temperature.
(b) In the compound of the present invention of the formula (I), the compound in which A is xe2x80x94SO2NR34xe2x80x94 or xe2x80x94NR35SO2xe2x80x94, and R1, R2 and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including amino and optionally protected hydroxy, that is the compound of the formula (I-B): 
wherein A2 is xe2x80x94SO2NR34xe2x80x94 or xe2x80x94NR35SO2xe2x80x94, the other symbols are as hereinbefore defined;
may be prepared by reacting the compound of the formula (IV-1): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (V-1): 
wherein all the symbols are as hereinbefore defined;
or by reacting the compound of the formula (IV-2): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (V-2): 
wherein all the symbols are as hereinbefore defined;
or in the case of the compound in which R6-1 and R7-1 are the group containing protected hydroxy, continually, may be prepared by deprotection.
The above reaction is known, for example, may be carried out by reacting sulfonic acid and acyl halide (e.g. oxalyl chloride or thionyl chloride) in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether, tetrahydrofuran, ethyl acetate) or without a solvent at xe2x88x9220xc2x0 C. to reflux temperature, and the obtained acyl halide derivative may be reacted with an amine in an organic solvent (e.g. chloroform, methylene chloride, diethyl ether or tetrahydrofuran) in the presence of a tertiary amine (e.g. pyridine, triethyl amine, dimethyl aniline or dimethylaminopyridine) at 0-40xc2x0 C.
The deprotection reaction is known, for example, may be carried out as method hereinbefore defined.
(c-1) In the compound of the present invention of the formula (I), the compound in which A is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94NR31CHR32-1xe2x80x94, and R1, R2 and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, E4 ring is not pyrrole, furan and thiophene, that is the compound of the formula (I-C-1): 
wherein
A3 is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94NR31CHR32-1xe2x80x94, in which
R32-1 is hydrogen, cyano, COO36-1, in which
R36-1 is C1-4 alkyl; or CONR37-1R38-1, in which
R37-1 and R38-1 each independently, is hydrogen, C1-4 alkyl, but both are not hydrogen at the same time; the other symbols are as hereinbefore defined;
may be prepared by alkylation the compound of the formula (VI): 
wherein
R39 is halogen atom, methansulfonyloxy or p-toluenesulfonyloxy, the other symbols are as hereinbefore defined;
with the compound of the formula (VII): 
wherein
R40 is xe2x80x94OHSH or xe2x80x94NHR31, the other symbols are as hereinbefore defined.
The above alkylation is known, for example, may be carried out in an inert organic solvent (e.g. tetrahydrofuran (THF), diethyl ether, methylene chloride, chloroform, carbon tetrachloride, pentane, hexane, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphric triamide (HMPA)), in the presence of an base (e.g. sodium hydride, potassium carbonate, triethylamine, pyridine, sodium iodide, cesium carbonate) at 0-80xc2x0 C.
In the case of the compound in which A3 or xe2x80x94NR31CH2xe2x80x94, it may be also prepared by subjecting the compound of the formula (XII): 
wherein all the symbols are as hereinbefore defined;
to pinner method.
The pinner method is known, for example, it may be carried out in an organic solvent (e.g. ethanol, methylene chloride) using hydrochloride at 0-50xc2x0 C., continually, in an organic solvent (e.g. methanol, ethanol) using ammonium gas at 0-50xc2x0 C.
(c-2) In the compound of the present invention of the formula (I), the compound in which A is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94NR31CHR32-1, and R1, R2 and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, E4 ring is pyrrole, furan or thiophene, that is the compound of the formula (I-C-2): 
wherein
A3 is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94 or xe2x80x94NR31CHR32-1xe2x80x94, the other symbols are as hereinbefore defined;
may be prepared by subjecting to condensation reaction, the compound of the formula (XI-b): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (IX):
H2Nxe2x80x94R1xe2x80x83xe2x80x83(IX)
wherein R1 is as hereinbefore defined.
The condensation reaction is known, for example, it may be carried out as method hereinbefore defined.
(d-1) In the compound of the present invention of the formula (I), the compound in which A is vinylene, ethynylene, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94NR33xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, when A is vinylene or ethynylene, then E4 ring is not pyrrole, furan and thiophene, that is the compound of the formula (I-D-1): 
wherein
A4 is vinylene, ethynylene, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94NR33xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94,
E4c ring is a same meaning as E4 ring, with the proviso that it is not pyrrole, furan and thiophene, when A is vinylene or ethynylene, the other symbols are as hereinbefore defined;
may be prepared by subjecting to condensation reaction, the compound of the formula (VIII): 
wherein
R41 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and the other symbols are as hereinbefore defined;
with the compound of the formula (IX):
H2Nxe2x80x94R1xe2x80x83xe2x80x83(IX)
xe2x80x83wherein R1 is as hereinbefore defined.
The above reaction is known, for example, the compound of the formula (VIII) may be carried out by reacting with the compound of the formula (IX) or salts thereof in an organic solvent (e.g. methanol, ethanol, acetonitrile, methylene chloride, diethyl ether, tetrahydrofuran, toluene, dimethylformamide) or without a solvent, optionally in the presence of an base (e.g. triethylamine, sodium hydride, sodium methoxide, sodium ethoxide) at 0xc2x0 C. to reflux temperature.
(d-2) In the compound of the present invention of the formula (I), the compound in which A is vinylene, ethynylene, and R3 are not groups including hydroxy, and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, E4 ring is pyrrole, furan or thiophene, that is the compound of the formula (I-D-2): 
wherein
A4-2 is vinylene, ethynylene, and the other symbols are as hereinbefore defined;
may be prepared by subjecting to condensation reaction, the compound of the formula (XI-c): 
wherein all the symbols are as hereinbefore defined;
with the compound of the formula (IX):
H2Nxe2x80x94R1xe2x80x83xe2x80x83(IX)
wherein R1 is as hereinbefore defined.
The condensation reaction is known, for example, it may be carried out as method hereinbefore defined.
(e) In the compound of the present invention of the formula (I), the compound in which A is ethylene, and R1, R2 and R3 are not groups including hydroxy; and R4 and R5 are groups excepting CONR12R13 and are not groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, and R6 and R7 are not groups including hydroxy and amino, that is the compound of the formula (I-E): 
wherein
A5 is ethylene, and the other symbols are as hereinbefore defined;
may be prepared by subjecting to reduction the compound in which A4 is vinylene or ethynylene in the compound of the formula (I-D-1), or the compound of the formula (I-D-2).
The above reduction reaction is known, for example, in an organic solvent (e.g. tetrahydrofuran, dioxane, diethyl ether, ethyl acetate, methanol, ethanol), using a catalyst (e.g. palladium on carbon, palladium, palladium hydroxide, palladium acetate, palladium black, platinum black, nickel or Raney-nickel), at ordinary or elevated pressure of hydrogen gas at 0-80xc2x0 C.
(f) In the compound of the present invention of the formula (I), R4 and R5 are groups excepting CONR12R13, R1, R2 and R3 are groups including hydroxy, or R4 and R5 are groups including xe2x80x94COOH, P(O)(OH)2 and tetrazol-5-yl, or R6 and R7 are groups including hydroxy and amino, that is the compound of the formula (I-F): 
wherein
R1-2, R2-2, R3-2, R6-3 and R7-3 each is the same meaning as R1, R2, R3, R6 and R7, R4-2 and R5-2 each is the same meaning as R4 and R5 excepting CONR12R13, with the proviso that at least one of R1-2, R2-2, R3-2, R4-2, R5-2, R6-3, and R7-3 is hydroxy, xe2x80x94COOH, amino, P(O)(OH)2, tetrazol-5-yl, or a group including them, the other symbols are as hereinbefore defined;
may be prepared by deprotection under an alkaline condition, deprotection under an acidic conditions and/or hydrogenolysis, the compound of the formula (I-A-1), (I-A-2), (I-B),(I-C-1), (I-C-2), (I-D-1), (I-D-2) or (I-E).
Deprotection under an alkaline condition is known, for example, may be carried out in an organic solvent (e.g. methanol, tetrahydrofuran, dioxane), using an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkaline earth metal hydroxide (e.g. calcium hydroxide) or a carbonate (e.g. sodium carbonate, potassium carbonate), or an aqueous solution thereof or mixture thereof at 0-40xc2x0 C.
Deprotection under acidic conditions, for example, may be carried out in a solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate, anisole) or without a solvent, using an organic acid (e.g. acetic acid, trifluoroacetic acid, methansulfonic acid, trimethylsilyl iodide), or an inorganic acid (e.g. hydrogen chloride) or a mixture thereof (e.g. hydrogen bromide acetic acid) at 0-90xc2x0 C.
Hydrogenolysis, for example, may be carried out in a solvent (e.g. tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol), in the presence of a catalyst (e.g. palladium on carbon, palladium, palladium hydroxide, palladium acetate, palladium black, platinum black, nickel or Raney-nickel), at ordinary or elevated pressure of hydrogen gas at 0-80xc2x0 C.
(g) In the compound of the present invention of the formula (I), R4 and R5 are CONR12R13, that is the compound of the formula (I-G): 
wherein
R4-3 and R5-3 each independently, is CONR12R13, and R1-2, R2-2, R3-2, R6-3 and R7-3 each is the same meaning as R1, R2, R3, R6 and R7, with the proviso that at least one of R1-2, R2-2, R3-2, R6-3 and R7-3 is hydroxy, xe2x80x94COOH, amino or a group including them, the other symbols are as hereinbefore defined;
may be prepared by amidation the compound in which at least one of R4 and R5 is xe2x80x94COOH or a group including it in the compound of the formula (I-F), with the compound of the formula (X):
NHR12R13xe2x80x83xe2x80x83(X)
wherein all the symbols are as hereinbefore defined.
Amidation is known, for example, it may be carried out by the same method as hereinbefore described.
As will be apparent to those skilled in the art, t-butyl or benzyl may be used as protecting groups for carboxyl, and t-butyl, benzyl, t-butyldimethylsilyl, trimethylsilyl may be used as protecting groups for hydroxy, but other groups which may be removed easily and selectively are also preferred. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991, may be used.
Benzyloxycarbonyl, t-butoxycarbonyl may be used as protecting groups for amino, but other groups which may be removed easily and selectively are also preferred.
t-Butyl or benzyl may be used as protecting groups for hydroxylamine, but other groups which may be removed easily and selectively are also preferred. For example xe2x80x94C(CH3)2xe2x80x94OCH3 may be used.
The desired compound of the present invention may be easily prepared using these protecting groups.
The compound of the formula (II), (III), (IV-1), (IV-2), (V-1), (V-2), (VI), (VII), (VIII), (IX), (X), (XI-a), (XI-b), (XI-c) and (XII) are known per se or may be prepared by known methods, or methods in the Examples.
For example, the compound of the formula (II), (V-1), (V-2), (VI), (VIII), (XI), and (XII) may be prepared by using a reaction depicted in following schemes.
Symbols in each schemes mean as follows, the other symbols are as hereinbefore defined.
L: OTf, halogen atom,
Tf: trifluoromethansulfonyl,
M: xe2x80x94B(OH)2, xe2x80x94Sn(C1-4 alkyl)3,
R42: a general protecting groups of amine,
R43: a general protecting groups of hydroxy,
Tf2O: trifluoromethansulfonic acid anhydrous,
HC(SMe)3: tris(methylthio)methane,
NBS: N-bromosuccinimide,
TMSCN: trimethylsilylcyanide,
HClaq: an aqueous solution of hydrochloric acid,
MsCl: methanesulfonyl chloride,
TsCl: p-toluenesulfonyl chloride,
A4-1: xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94NR33xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94,
A6: xe2x80x94NR30COxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94NR31CHR32-1xe2x80x94, vinylene, ethylene,
NaSH: sodium bisulfate,
Mel: methyl iodide,
MeOH: methanol. 
The starting materials in each scheme are known per se or may be prepared by known methods.
The reaction in each scheme are carried out by known methods.
The other starting materials and reagents in the present invention are known per se or may be prepared by known methods.
Pharmacological Activities
(1) FVIIa inhibitory activity
10 xcexcl of the compound of the present invention in 10% DMSO were added to 65 xcexcl of the buffer solution including FVIIa (ADI#407, final 10 nM), tissue factor (ADI#4500, final 10 nM) and calcium chloride. The mixture was incubated for 10 minutes at 37xc2x0 C., then 25 xcexcl of 2 mM H-D-Ile-Pro-Arg-pNA (Chromogenix S-2288) was added (total volume 100 xcexcl). The absorbance was measured at 405 nm at regular time intervals, and an initial velocity was calculated. The control value was measured with 10% of DMSO. Inhibitory activity was expressed as a 50% inhibition of control (IC50).
The final concentration of calcium chloride and S-2288 were 2 mM and 0.5 mM respectively. The buffer solution consisted of 50 mM tris-hydrochloric acid buffer (pH 7.5) containing 0.2% PEG6000 and 150 mM sodium chloride.
These results are shown in Table 28.
(2) Anticoagulant effect on the prothrombin time (PT) and the activated partial thromboplastin time (APTT)
PT is assayed by addition of tissue factor and indicates the coagulant activity of the extrinsic pathway, and APTT is assayed by addition of negative charged substances and indicates the coagulant activity of the intrinsic pathway.
The assay method was as follows.
Purified human plasma (verify reference plasma, organon technica) and the compound of the present invention in 10% DMSO solution were mixed at the rate of 9:1.
(a) PT determination
An automatic coagulation determination device (Sysmex CA5000) was used for the measurement of blood coagulation time, using the plasma described above and thromboplastin C (Dade).
The control value was determined by adding solvent without the compound of the present invention. The concentration of the compound of the present invention at which the coagulation time prolonged two time of the control (PTCT2), was calculated.
(b) APTT determination
An automatic coagulation determination device (Sysmex CA5000) was used for the measurement of blood coagulation time, using the plasma described above, datefy APTT (Dade) and 20 mM calcium chloride.
The control value was determined by adding solvent without the compound of the present invention. The concentration of the compound of the present invention at which the coagulation time prolonged two time of the control (APTTCT2), was calculated, and an extension rate (%) of APTT on PTCT2 were estimated.
An extension rate of APTT on PTCT2 of the compound of the present invention was not effective.
Toxicity
The toxicity of the compounds of the present invention is very low and therefore the compounds may be considered safe for pharmaceutical use.
Utility
The formula (I) of amidino derivatives, their non-toxic salts and hydrates have an inhibitory activity for a blood coagulation factor VIIa and are useful for treatment and/or prevention of several angiopathologic diseases due to the hypercoagulability, such as disseminated intravascular coagulation, coronary thrombosis (e.g. acute myocardial infarction, unstable angina), cerebral infarction, cerebral embolism, transient ischemic attack, diseases caused by cerebrovascular disorders, pulmonary vascular diseases (e.g. pulmonary infarction, pulmonary embolism), deep venous thrombosis, peripheral arterial obstruction, thrombosis after artificial vascular transplantation and artificial valve transplantation, post-operative thrombosis, reobstruction and restenosis after coronary artery bypass operation, reobstruction and restenosis after PTCA (percutaneous transluminal coronary angioplasty) or PTCR (percutaneous transluminal coronary recanalization), thrombosis by extracorporeal circulation and procoagulative diseases such as glomerlonephriitis.
Application for Pharmaceuticals
For the purpose above described, the compounds of formulae (I) of the present invention, non-toxic salts, acid addition salts or hydrates thereof may be normally administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 0.1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered in the form of, for example, solid forms for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules.
In such solid forms, one or more of the active compound(s) may be admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose, starch), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants (such as cellulose calcium glycolate), lubricants (such as magnesium stearate), stabilizing agents, and solution adjuvants (such as glutamic acid or aspartic acid) and prepared according to methods well known in normal pharmaceutical practice. The solid forms may, if desired, be coated with coating agents (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions and emulsions, syrups and elixirs. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulized into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof. Besides such liquid forms may also comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulized into solvent(s). The solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.
Injections may comprise some additives, such as stabilizing agents, solution adjuvants (such as glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)), suspending agents, emulsifying agents, soothing agent, buffering agents, preservative. They may be sterilized at a final step, or may be prepared and compensated according to sterile methods. They may also be manufactured in the form of sterile solid forms which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by methods known per se. Sprays may comprise additional substances other than diluents, such as stabilizing agents (such as sodium sulfate), isotonic buffers (such as sodium chloride, sodium citrate or citric acid). For preparation of such sprays, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.